Heart failure (HF) is the leading cause of mortality and morbidity, which afflicts 5.7 million Americans. HF management includes surgery, implantable device and pharmacological therapy targeting angiotensin and adrenergic signaling. Numerous animal models of heart failure have been generated and studied for decades in effort to identify therapeutic targets for treatment of human HF patients. However, it is becoming increasingly evident that this strategy has yielded limited therapeutic options for the treatment o HF. Significant genetic, molecular, cellular, anatomical, and systemic differences among species are likely to be responsible for failure of translation from cell lines and animal models t humans. Cardiac rhythm disorders are striking examples of such translational failure. Despite deep knowledge of the biophysical properties of numerous ion channels, pumps, and exchangers gained over half a century of research conducted at huge expense, current pharmacological therapies used to treat arrhythmias are nonspecific and often ineffective. The main reason for this failure is the complexity of human cardiac physiology at the molecular, cellular and tissue levels. It is paradoxical, but we know much more about ion channels and action potentials in the mouse, rat, guinea pig, rabbit, and canine as compared to our own species - Homo sapiens. We have recently developed a program, which allows investigation of the mechanisms of arrhythmogenic remodeling in live human hearts in vitro. In this project we will investigate a number of mechanistic hypothesis linking HF and arrhythmia in live cardiac tissue from donors and patients with HF. In summary, we will develop, refine and extend experimental methodology, which is currently applied only to animal cardiac preparations in basic physiology laboratories, to deepen our understanding of human cardiac pathophysiology. This approach will modify and enhance the currently dominant translational paradigm and provide new important directions of research, which will stimulate and reinvigorate a biomedical research community that has ignored human physiology and thus delayed effective translation of needed therapies for HF and sudden cardiac death.

Public Health Relevance

Our project aims to bridge the gap between fundamental discoveries in animal models of human heart failure and its validation in clinical trials. We will develop methodology to produce critically important new physiological knowledge about the cardiac function of the human species, using explanted hearts of transplantation patients and donor hearts rejected from transplantation. These precious gifts of live human hearts will yield critically important new knowledge about pathological processes occurring during heart failure in humans that lead to sudden cardiac death of hundreds of thousands of patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL114395-02S1
Application #
8676188
Study Section
Special Emphasis Panel (ZRG1-CVRS-E (02))
Program Officer
Boineau, Robin
Project Start
2012-08-15
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$96,257
Indirect Cost
$32,930
Name
Washington University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Koh, Ahyeon; Gutbrod, Sarah R; Meyers, Jason D et al. (2016) Ultrathin Injectable Sensors of Temperature, Thermal Conductivity, and Heat Capacity for Cardiac Ablation Monitoring. Adv Healthc Mater 5:373-81
Ng, Fu Siong; Efimov, Igor R (2016) Letter by Ng and Efimov Regarding Article, "Electrophysiological Effects of Selective Atrial Coronary Artery Occlusion in Humans". Circulation 134:e397-e398
Holzem, Katherine M; Gomez, Juan F; Glukhov, Alexey V et al. (2016) Reduced response to IKr blockade and altered hERG1a/1b stoichiometry in human heart failure. J Mol Cell Cardiol 96:82-92
Kang, C; Qiao, Y; Li, G et al. (2016) Human Organotypic Cultured Cardiac Slices: New Platform For High Throughput Preclinical Human Trials. Sci Rep 6:28798
Holzem, Katherine M; Vinnakota, Kalyan C; Ravikumar, Vinod K et al. (2016) Mitochondrial structure and function are not different between nonfailing donor and end-stage failing human hearts. FASEB J 30:2698-707
Xu, Lizhi; Gutbrod, Sarah R; Ma, Yinji et al. (2015) Materials and fractal designs for 3D multifunctional integumentary membranes with capabilities in cardiac electrotherapy. Adv Mater 27:1731-7
Lang, Di; Holzem, Katherine; Kang, Chaoyi et al. (2015) Arrhythmogenic remodeling of β2 versus β1 adrenergic signaling in the human failing heart. Circ Arrhythm Electrophysiol 8:409-19
Ripplinger, Crystal M; Efimov, Igor R (2015) Dual Vm/Ca imaging of premature ventricular contractions: bridging the gap of anatomical scales. Circ Arrhythm Electrophysiol 8:529-30
Sulkin, Matthew S; Boukens, Bas J; Tetlow, Megan et al. (2014) Mitochondrial depolarization and electrophysiological changes during ischemia in the rabbit and human heart. Am J Physiol Heart Circ Physiol 307:H1178-86
Xu, Lizhi; Gutbrod, Sarah R; Bonifas, Andrew P et al. (2014) 3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium. Nat Commun 5:3329

Showing the most recent 10 out of 35 publications